CN103442709B - Slow down liver cancer to deteriorate, improve liver function, improve liver fibrosis, improve hepatic sclerosis, improve liver inflammation and promote the pharmaceutical composition of damaged liver regeneration - Google Patents
Slow down liver cancer to deteriorate, improve liver function, improve liver fibrosis, improve hepatic sclerosis, improve liver inflammation and promote the pharmaceutical composition of damaged liver regeneration Download PDFInfo
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- CN103442709B CN103442709B CN201180069476.5A CN201180069476A CN103442709B CN 103442709 B CN103442709 B CN 103442709B CN 201180069476 A CN201180069476 A CN 201180069476A CN 103442709 B CN103442709 B CN 103442709B
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- 244000274883 Urtica dioica Species 0.000 description 1
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
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- 238000000540 analysis of variance Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
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- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
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- 235000007242 delphinidin Nutrition 0.000 description 1
- FFNDMZIBVDSQFI-UHFFFAOYSA-N delphinidin chloride Chemical compound [Cl-].[O+]=1C2=CC(O)=CC(O)=C2C=C(O)C=1C1=CC(O)=C(O)C(O)=C1 FFNDMZIBVDSQFI-UHFFFAOYSA-N 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
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- QOLIPNRNLBQTAU-UHFFFAOYSA-N flavan Chemical class C1CC2=CC=CC=C2OC1C1=CC=CC=C1 QOLIPNRNLBQTAU-UHFFFAOYSA-N 0.000 description 1
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- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
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- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
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- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
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- 238000004989 laser desorption mass spectroscopy Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
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- 239000002184 metal Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
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- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
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- 239000011701 zinc Substances 0.000 description 1
Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/87—Vitaceae or Ampelidaceae (Vine or Grape family), e.g. wine grapes, muscadine or peppervine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
- C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The present invention provides one kind and slowing down liver cancer deterioration, improve liver function, improve liver fibrosis, improve hepatic sclerosis, improving liver inflammation and the pharmaceutical composition of promotion damaged liver regeneration, including:The procyanidine of one effective quantity;And pharmaceutically acceptable a carrier or salt, the wherein monomer of the procyanidine have following chemical formula.In above-mentioned chemical formula, work as R1For OCH3When, R2For OH, R3For H, work as R1For OH when, R2For H, R3For H, work as R1For OH when, R2For OH, R3For H or work as R1For OH when, R2For OH, R3For OH, R4For 3 (α) OH, 3 (β) OH, 3 (α) O sugar or 3 (β) O sugar.
Description
Technical field
Present invention is directed to a kind of pharmaceutical composition, in particular to one kind slow down liver cancer deteriorate, improve liver function,
Improve liver fibrosis, improve hepatic sclerosis, improve liver inflammation and promote the pharmaceutical composition of damaged liver regeneration.
Background technology
Liver cancer male in the global cancer cause of the death is number five, women ranking the 8th.Liver cancer is almost not easy in early stage
It finds, therefore, is often delayed best occasion for the treatment.It is clinically best treatment means with surgical resection or liver transplant,
But most hepatocarcinoma patient when being diagnosed suffering from hepatic cancer more belong to late period, the only 15% acceptable operation excision of patient,
And its cure rate is less than 5%.In addition, have using therapies such as embolism, electricity burning, radiation, but its high recurrence rate is up to 8 one-tenth or more.
Clinic has symptom and is diagnosed as liver cancer person, average viability only about 6 months, it is seen that not only the death rate is high for liver cancer, prognosis
Also excessively poor.Currently, the common chemotherapeutic agent such as Fluorouracil, Pirarubicin of liver cancer, Oxaliplatin,
Cisplatin etc., curative effect is very limited.Currently, newest therapy is the target drug using a variety of kinase inhibitors(Sorafenib), for treating advanced hepatocellular carcinoma or primary carcinoma of liver, liver cancer patient Average Survival can be extended
Time.Global treatment of cancer market scale in 2008 is up to 53,100,000,000 dollars (Nature Review in Cancer), and liver cancer
Treating relevant market, there are about 25.2 hundred million dollars, it is seen that the correlation new drug development for the treatment of liver cancer has very big market potential.
Invention content
One of present invention embodiment provides one kind and slowing down liver cancer deterioration, improve liver function, improve liver fibrosis, improve liver
Hardening improves liver inflammation, promotes damaged liver regeneration and/or reverses the pharmaceutical composition of liver fibrosis, including:One effective quantity it
Procyanidine;And pharmaceutically acceptable a carrier or salt, the wherein monomer of the procyanidine have following chemical formula.
In above-mentioned chemical formula, work as R1For OCH3When, R2For OH, R3For H, work as R1For OH when, R2For H, R3For H, work as R1For OH
When, R2For OH, R3For H or work as R1For OH when, R2For OH, R3For OH, R4For 3- (α)-OH, 3- (β)-OH, 3- (α)-O-sugar or
3-(β)-O-sugar。
Pharmaceutical composition (BEL-X) of the present invention can be applied to the treatment of various liver diseases through experiment test discovery, including
(1) by the caused liver cancer of chronic hepatitis b virus or hepatitis C virus infection, pharmaceutical composition (BEL-X) of the present invention can be single
Solely use or as other various cures auxiliary therapeutical agent, can improve and be promoted the liver function of liver cancer sufferer, slow down liver
Cancer deteriorates time-histories, and operability and success rate of operation can be carried out by improving liver cancer sufferer, reduced Postoperative recurrent rate, can be increased liver cancer sufferer
Survival rate with extend the time-to-live, meanwhile, can also promote the quality of the life of liver cancer sufferer.(2) pharmaceutical composition of the present invention
(BEL-X) it can be used alone or merge with other clinical treatment drugs using treating liver fibrosis sufferer.(3) drug of the present invention
Composition (BEL-X) be can be used alone or be merged with other clinical treatment drugs using treating liver inflammation sufferer, such as:Fat
Liver disease prevents the generation of hepatic sclerosis and liver cancer to improve its liver function.
That is, the present invention is for example following.
1. one kind slowing down the pharmaceutical composition of liver cancer deterioration, including:
The monomer of the procyanidine of one effective quantity, the procyanidine has following chemical formula:
Wherein, work as R1For OCH3When, R2For OH, R3For H, work as R1For OH when, R2For H, R3For H, work as R1For OH when, R2For OH,
R3For H or work as R1For OH when, R2For OH, R3For OH, R4For 3- (α)-OH, 3- (β)-OH, 3- (α)-O-sugar or 3- (β)-O-
sugar;And
One pharmaceutically acceptable carrier or salt.
2. the pharmaceutical composition for slowing down liver cancer deterioration according to item 1, wherein the monomer of the procyanidine is with C4, C8 carbon
Key, C4, C6 carbon key or C2, C7 oxygen key are connected with each other.
3. the pharmaceutical composition for slowing down liver cancer deterioration according to item 1, the wherein degree of polymerization of the procyanidine between 2~
30。
4. the pharmaceutical composition for slowing down liver cancer deterioration according to item 1, the monomer of the wherein procyanidine be included in C2,
R the or S optical isomeric compounds of the positions C3 or C4.
5. the monomer of the pharmaceutical composition for slowing down liver cancer deterioration according to item 1, the wherein procyanidine includes flavones
Class compound.
6. the pharmaceutical composition for slowing down liver cancer deterioration according to item 5, the wherein flavone compound include catechin
(catechin), epicatechin (epicatechin), epiafzelechin (epiafzelechin), gallocatechin
(gallocatechin), galloepicatechin, epigallocatechin (epigallocatechin), gallates, Huang
Keto-alcohol (flavonols), flavandiols (flavandiols), leucocyanidin (leucocyanidins) or anthocyanidin
(procynidins)。
7. the monomer of the pharmaceutical composition for slowing down liver cancer deterioration according to item 1, the wherein procyanidine includes flavane-
3- alcohol (flavan-3-ol).
8. the pharmaceutical composition for slowing down liver cancer deterioration according to item 1, the wherein procyanidine are extracted from a plant.
9. the pharmaceutical composition for slowing down liver cancer deterioration according to item 8, the wherein plant include Ericaceae
(Ericaceae), the rose family (Rosaceae), Pinaceae (Pinaceae), Vitaceae (Vitaceae) or Urticaceae
(Urticaceae) plant.
10. the pharmaceutical composition for slowing down liver cancer deterioration according to item 9, the wherein plant of the Urticaceae (Urticaceae)
Object includes mountain ramie.
11. a kind of pharmaceutical composition improving liver function, including:
The monomer of the procyanidine of one effective quantity, the procyanidine has following chemical formula:
Wherein, work as R1For OCH3When, R2For OH, R3For H, work as R1For OH when, R2For H, R3For H, work as R1For OH when, R2For OH,
R3For H or work as R1For OH when, R2For OH, R3For OH, R4For 3- (α)-OH, 3- (β)-OH, 3- (α)-O-sugar or 3- (β)-O-
sugar;And
One pharmaceutically acceptable carrier or salt.
12. the pharmaceutical composition of the improvement liver function according to item 11, wherein the monomer of the procyanidine is with C4, C8 carbon
Key, C4, C6 carbon key or C2, C7 oxygen key are connected with each other.
13. the pharmaceutical composition of the improvement liver function according to item 11, the wherein degree of polymerization of the procyanidine between 2~
30。
14. the pharmaceutical composition of the improvement liver function according to item 11, the monomer of the wherein procyanidine be included in C2,
R the or S optical isomeric compounds of the positions C3 or C4.
15. the monomer of the pharmaceutical composition of the improvement liver function according to item 11, the wherein procyanidine includes flavones
Class compound.
16. the pharmaceutical composition of the improvement liver function according to item 15, the wherein flavone compound include catechin
(catechin), epicatechin (epicatechin), epiafzelechin (epiafzelechin), gallocatechin
(gallocatechin), galloepicatechin, epigallocatechin (epigallocatechin), gallates, Huang
Keto-alcohol (flavonols), flavandiols (flavandiols), leucocyanidin (leucocyanidins) or anthocyanidin
(procynidins)。
17. the monomer of the pharmaceutical composition of the improvement liver function according to item 11, the wherein procyanidine includes flavane-
3- alcohol (flavan-3-ol).
18. the pharmaceutical composition of the improvement liver function according to item 11, the wherein procyanidine are extracted from a plant.
19. the pharmaceutical composition of the improvement liver function according to item 18, the wherein plant include Ericaceae
(Ericaceae), the rose family (Rosaceae), Pinaceae (Pinaceae), Vitaceae (Vitaceae) or Urticaceae
(Urticaceae) plant.
20. the pharmaceutical composition of the improvement liver function according to item 19, the wherein plant of the Urticaceae (Urticaceae)
Object includes mountain ramie.
21. a kind of pharmaceutical composition improving liver fibrosis, including:
The monomer of the procyanidine of one effective quantity, the procyanidine has following chemical formula:
Wherein, work as R1For OCH3When, R2For OH, R3For H, work as R1For OH when, R2For H, R3For H, work as R1For OH when, R2For OH,
R3For H or work as R1For OH when, R2For OH, R3For OH, R4For 3- (α)-OH, 3- (β)-OH, 3- (α)-O-sugar or 3- (β)-O-
sugar;And
One pharmaceutically acceptable carrier or salt.
22. the pharmaceutical composition of the improvement liver fibrosis according to item 21, wherein the monomer of the procyanidine is with C4, C8
Carbon key, C4, C6 carbon key or C2, C7 oxygen key are connected with each other.
23. the pharmaceutical composition of the improvement liver fibrosis according to item 21, wherein the degree of polymerization of the procyanidine is between 2
~30.
24. the pharmaceutical composition of the improvement liver fibrosis according to item 21, the monomer of the wherein procyanidine are included in
R the or S optical isomeric compounds of the position C2, C3 or C4.
25. the pharmaceutical composition of the improvement liver fibrosis according to item 21, the wherein monomer of the procyanidine include Huang
Ketone compounds.
26. the pharmaceutical composition of the improvement liver fibrosis according to item 25, the wherein flavone compound include catechu
Plain (catechin), epicatechin (epicatechin), epiafzelechin (epiafzelechin), gallocatechin
(gallocatechin), galloepicatechin, epigallocatechin (epigallocatechin), gallates, Huang
Keto-alcohol (flavonols), flavandiols (flavandiols), leucocyanidin (leucocyanidins) or anthocyanidin
(procynidins)。
27. the pharmaceutical composition of the improvement liver fibrosis according to item 21, the wherein monomer of the procyanidine include Huang
Alkane -3- alcohol (flavan-3-ol).
28. the pharmaceutical composition of the improvement liver fibrosis according to item 21, the wherein procyanidine are extracted from a plant.
29. the pharmaceutical composition of the improvement liver fibrosis according to item 28, the wherein plant include Ericaceae
(Ericaceae), the rose family (Rosaceae), Pinaceae (Pinaceae), Vitaceae (Vitaceae) or Urticaceae
(Urticaceae) plant.
30. the pharmaceutical composition of the improvement liver fibrosis according to item 29, the wherein Urticaceae (Urticaceae) it
Plant includes mountain ramie.
31. a kind of pharmaceutical composition improving hepatic sclerosis, including:
The monomer of the procyanidine of one effective quantity, the procyanidine has following chemical formula:
Wherein, work as R1For OCH3When, R2For OH, R3For H, work as R1For OH when, R2For H, R3For H, work as R1For OH when, R2For OH,
R3For H or work as R1For OH when, R2For OH, R3For OH, R4For 3- (α)-OH, 3- (β)-OH, 3- (α)-O-sugar or 3- (β)-O-
sugar;And
One pharmaceutically acceptable carrier or salt.
32. the pharmaceutical composition of the improvement hepatic sclerosis according to item 31, wherein the monomer of the procyanidine is with C4, C8 carbon
Key, C4, C6 carbon key or C2, C7 oxygen key are connected with each other.
33. the pharmaceutical composition of the improvement hepatic sclerosis according to item 31, the wherein degree of polymerization of the procyanidine between 2~
30。
34. the pharmaceutical composition of the improvement hepatic sclerosis according to item 31, the monomer of the wherein procyanidine be included in C2,
R the or S optical isomeric compounds of the positions C3 or C4.
35. the monomer of the pharmaceutical composition of the improvement hepatic sclerosis according to item 31, the wherein procyanidine includes flavones
Class compound.
36. the pharmaceutical composition of the improvement hepatic sclerosis according to item 35, the wherein flavone compound include catechin
(catechin), epicatechin (epicatechin), epiafzelechin (epiafzelechin), gallocatechin
(gallocatechin), galloepicatechin, epigallocatechin (epigallocatechin), gallates, Huang
Keto-alcohol (flavonols), flavandiols (flavandiols), leucocyanidin (leucocyanidins) or anthocyanidin
(procynidins)。
37. the monomer of the pharmaceutical composition of the improvement hepatic sclerosis according to item 31, the wherein procyanidine includes flavane-
3- alcohol (flavan-3-ol).
38. the pharmaceutical composition of the improvement hepatic sclerosis according to item 31, the wherein procyanidine are extracted from a plant.
39. the pharmaceutical composition of the improvement hepatic sclerosis according to item 38, the wherein plant include Ericaceae
(Ericaceae), the rose family (Rosaceae), Pinaceae (Pinaceae), Vitaceae (Vitaceae) or Urticaceae
(Urticaceae) plant.
40. the pharmaceutical composition of the improvement hepatic sclerosis according to item 39, the wherein plant of the Urticaceae (Urticaceae)
Object includes mountain ramie.
41. a kind of pharmaceutical composition improving liver inflammation, including:
The monomer of the procyanidine of one effective quantity, the procyanidine has following chemical formula:
Wherein, work as R1For OCH3When, R2For OH, R3For H, work as R1For OH when, R2For H, R3For H, work as R1For OH when, R2For OH,
R3For H or work as R1For OH when, R2For OH, R3For OH, R4For 3- (α)-OH, 3- (β)-OH, 3- (α)-O-sugar or 3- (β)-O-
sugar;And
One pharmaceutically acceptable carrier or salt.
42. the pharmaceutical composition of the improvement liver inflammation according to item 41, wherein the monomer of the procyanidine is with C4, C8 carbon
Key, C4, C6 carbon key or C2, C7 oxygen key are connected with each other.
43. the pharmaceutical composition of the improvement liver inflammation according to item 41, the wherein degree of polymerization of the procyanidine between 2~
30。
44. the pharmaceutical composition of the improvement liver inflammation according to item 41, the monomer of the wherein procyanidine be included in C2,
R the or S optical isomeric compounds of the positions C3 or C4.
45. the pharmaceutical composition of the improvement liver inflammation according to item 41, the monomer of the wherein procyanidine includes flavones
Class compound.
46. the pharmaceutical composition of the improvement liver inflammation according to item 45, the wherein flavone compound includes catechin
(catechin), epicatechin (epicatechin), epiafzelechin (epiafzelechin), gallocatechin
(gallocatechin), galloepicatechin, epigallocatechin (epigallocatechin), gallates, Huang
Keto-alcohol (flavonols), flavandiols (flavandiols), leucocyanidin (leucocyanidins) or anthocyanidin
(procynidins)。
47. the pharmaceutical composition of the improvement liver inflammation according to item 41, the monomer of the wherein procyanidine includes flavane-
3- alcohol (flavan-3-ol).
48. the pharmaceutical composition of the improvement liver inflammation according to item 41, the wherein procyanidine are extracted from a plant.
49. the pharmaceutical composition of the improvement liver inflammation according to item 48, the wherein plant includes Ericaceae
(Ericaceae), the rose family (Rosaceae), Pinaceae (Pinaceae), Vitaceae (Vitaceae) or Urticaceae
(Urticaceae) plant.
50. the pharmaceutical composition of the improvement liver inflammation according to item 49, the wherein plant of the Urticaceae (Urticaceae)
Object includes mountain ramie.
51. a kind of pharmaceutical composition of promotion damaged liver regeneration, including:
The monomer of the procyanidine of one effective quantity, the procyanidine has following chemical formula:
Wherein, work as R1For OCH3When, R2For OH, R3For H, work as R1For OH when, R2For H, R3For H, work as R1For OH when, R2For OH,
R3For H or work as R1For OH when, R2For OH, R3For OH, R4For 3- (α)-OH, 3- (β)-OH, 3- (α)-O-sugar or 3- (β)-O-
sugar;And
One pharmaceutically acceptable carrier or salt.
52. the pharmaceutical composition of the promotion damaged liver regeneration according to item 51, the wherein monomer of the procyanidine with
C4, C8 carbon key, C4, C6 carbon key or C2, C7 oxygen key are connected with each other.
53. the pharmaceutical composition of the promotion damaged liver regeneration according to item 51, the wherein degree of polymerization of the procyanidine
Between 2~30.
54. the pharmaceutical composition of the promotion damaged liver regeneration according to item 51, wherein the monomer packet of the procyanidine
Include R the or S optical isomeric compounds in the position C2, C3 or C4.
55. the pharmaceutical composition of the promotion damaged liver regeneration according to item 51, wherein the monomer packet of the procyanidine
Include flavone compound.
56. the pharmaceutical composition of the promotion damaged liver regeneration according to item 55, the wherein flavone compound include
Catechin (catechin), epicatechin (epicatechin), epiafzelechin (epiafzelechin), gallic acid
Theine (gallocatechin), galloepicatechin, epigallocatechin (epigallocatechin),
Gallates, flavonols (flavonols), flavandiols (flavandiols), leucocyanidin (leucocyanidins)
Or anthocyanidin (procynidins).
57. the pharmaceutical composition of the promotion damaged liver regeneration according to item 51, wherein the monomer packet of the procyanidine
Include flavan-3-alcohol (flavan-3-ol).
58. the pharmaceutical composition of the promotion damaged liver regeneration according to item 51, the wherein procyanidine are extracted from one
Plant.
59. the pharmaceutical composition of the promotion damaged liver regeneration according to item 58, the wherein plant includes Ericaceae
(Ericaceae), the rose family (Rosaceae), Pinaceae (Pinaceae), Vitaceae (Vitaceae) or Urticaceae
(Urticaceae) plant.
60. the pharmaceutical composition of the promotion damaged liver regeneration according to item 59, the wherein Urticaceae
(Urticaceae) plant includes mountain ramie.
61. a kind of pharmaceutical composition reversing liver fibrosis, including:
The monomer of the procyanidine of one effective quantity, the procyanidine has following chemical formula:
Wherein, work as R1For OCH3When, R2For OH, R3For H, work as R1For OH when, R2For H, R3For H, work as R1For OH when, R2For OH,
R3For H or work as R1For OH when, R2For OH, R3For OH, R4For 3- (α)-OH, 3- (β)-OH, 3- (α)-O-sugar or 3- (β)-O-
sugar;And
One pharmaceutically acceptable carrier or salt.
62. the pharmaceutical composition of the reverse liver fibrosis according to item 61, wherein the monomer of the procyanidine is with C4, C8
Carbon key, C4, C6 carbon key or C2, C7 oxygen key are connected with each other.
63. the pharmaceutical composition of the reverse liver fibrosis according to item 61, wherein the degree of polymerization of the procyanidine is between 2
~30.
64. the pharmaceutical composition of the reverse liver fibrosis according to item 61, the monomer of the wherein procyanidine are included in
R the or S optical isomeric compounds of the position C2, C3 or C4.
65. the pharmaceutical composition of the reverse liver fibrosis according to item 61, the wherein monomer of the procyanidine include Huang
Ketone compounds.
66. the pharmaceutical composition of the reverse liver fibrosis according to item 65, the wherein flavone compound include catechu
Plain (catechin), epicatechin (epicatechin), epiafzelechin (epiafzelechin), gallocatechin
(gallocatechin), galloepicatechin, epigallocatechin (epigallocatechin), gallates, Huang
Keto-alcohol (flavonols), flavandiols (flavandiols), leucocyanidin (leucocyanidins) or anthocyanidin
(procynidins)。
67. the pharmaceutical composition of the reverse liver fibrosis according to item 61, the wherein monomer of the procyanidine include Huang
Alkane -3- alcohol (flavan-3-ol).
68. the pharmaceutical composition of the reverse liver fibrosis according to item 61, the wherein procyanidine are extracted from a plant.
69. the pharmaceutical composition of the reverse liver fibrosis according to item 68, the wherein plant include Ericaceae
(Ericaceae), the rose family (Rosaceae), Pinaceae (Pinaceae), Vitaceae (Vitaceae) or Urticaceae
(Urticaceae) plant.
70. the pharmaceutical composition of the reverse liver fibrosis according to item 69, the wherein Urticaceae (Urticaceae) it
Plant includes mountain ramie.
71. pharmaceutical composition described in any one of 1~70 slows down liver cancer in manufacture and deteriorates, improves liver function, improves
Liver fibrosis improves hepatic sclerosis, improves liver inflammation, damaged liver is promoted to regenerate and/or reverse the use in the drug of liver fibrosis
On the way.
72. the pharmaceutical composition described in any one of 1~70 deteriorates for slowing down liver cancer, improves liver function, improves liver
Fibrosis improves hepatic sclerosis, improves liver inflammation, promotes damaged liver regeneration and/or reverse liver fibrosis.
For the above-mentioned objects, features and advantages of the present invention can be clearer and more comprehensible, a preferred embodiment cited below particularly, and match
Attached drawing is closed, is described in detail below.
Description of the drawings
Fig. 1 represents 3- flavanols (3-flavanol), 3,4- flavanols (3,4-flavanol), catechin
(catechin), epicatechin (epicatechin).
Fig. 2 a and Fig. 2 b represent 95% alcoholic extract of procyanidine mountain ramie, the thermal decomposition of the procyanidine after repurity
Gas chromatography mass spectrometry figure.
Fig. 3 represents 95% alcoholic extract of mountain ramie, the infrared Absorption spectrogram of the procyanidine after repurity.
Fig. 4 a and 4b represents 95% alcoholic extract of mountain ramie, the efficient liquid of the procyanidine of the procyanidine after repurity
The mutually positive/negative mass spectrogram of mass spectrum of chromatography.
Fig. 5 a-c represent 95% alcoholic extract of mountain ramie, 13C-NMR and the 1H-NMR figure of the procyanidine after repurity
Spectrum.
Fig. 6 a and 6b show according to the inspection collection of illustrative plates of 1HNMR and 13CNMR, the procyanidine macromolecule of present invention purifying it
Monomer links based on 4-8, and the connection unit of 4-8 and 4-6 is respectively as shown in Fig. 6 a and 6b.
Fig. 7 a-c represent 95% alcoholic extract of mountain ramie, the procyanidine medium assisted laser desorption ion after repurity
Change mass-spectrogram.
Fig. 8 systems show pharmaceutical composition (BEL-X) of the present invention to hepatitis B virus X trangenic mice induced hepatocellular carcinoma survival rates
Influence.
Fig. 9 systems show pharmaceutical composition (BEL-X) of the present invention to hepatitis B virus X trangenic mice liver cancer deterioration degree it
It influences, is assessed with liver weight/weight ratio.
Figure 10 systems show pharmaceutical composition (BEL-X) of the present invention to hepatitis B virus X trangenic mice induced hepatocellular carcinoma liver functions
Influence, assessed with liver function Index A LT.
Figure 11 systems show pharmaceutical composition (BEL-X) of the present invention to hepatitis B virus X trangenic mice induced hepatocellular carcinoma liver functions
Influence, assessed with liver function Index A ST.
Figure 12 systems show pharmaceutical composition (BEL-X) of the present invention to protection chemicals DEN inductions rat liver fibrosis it
It influences, is assessed with hydroxyproline content (hydroxyproline).
Figure 13 systems show pharmaceutical composition (BEL-X) of the present invention to protection chemicals DEN inductions rat liver fibrosis it
It influences, is assessed with α-SMA stained areas.
Figure 14 systems show that pharmaceutical composition (BEL-X) of the present invention induces chemicals DEN the influence of rat liver fibrosis,
It is assessed with hydroxyproline content.
The systems of Figure 15~16 show that pharmaceutical composition (BEL-X) of the present invention induces rat liver fibrosis/liver to chemicals DEN
The influence of cancer survival rate.
Figure 17 systems show that pharmaceutical composition (BEL-X) of the present invention induces rat liver fibrosis liver regeneration to chemicals DEN
Influence, with liver volume regeneration ratio assessed.
Specific implementation mode
The present invention slows down liver cancer deterioration, improvement using procyanidine as the active ingredient of pharmaceutical composition (BEL-X), to reach
Liver function improves liver fibrosis, improves hepatic sclerosis, improves liver inflammation and promotes the purpose of damaged liver regeneration.
The present invention can go out procyanidine from a plant extraction, have and slow down liver cancer deterioration, improve liver function, improve liver fibre
Dimensionization improves the effect of hepatic sclerosis, improvement liver inflammation and promotion damaged liver regeneration.In one embodiment, the plant used can
Including Ericaceae (Ericaceae), the rose family (Rosaceae), Pinaceae (Pinaceae), Vitaceae (Vitaceae) or nettle
The plant of numb section (Urticaceae), preferably the mountain ramie of Urticaceae (Urticaceae).And the extraction part of plant can wrap
Include root, stem, leaf and/or fruit.
The present invention can general prior art method progress plant extraction.In one embodiment, by the root of a plant, stem, leaf and/
Or be sliced or ground after fruit drying, later, plant is extracted with an extract liquor.In one embodiment, select with
The root and/or stem of mountain ramie are extracted.
The solution that water or water are mixed with opposed polarity solvent may be selected in above-mentioned extract liquor.It can be wrapped with the solvent of water opposed polarity
Include alcohol, acetone, methanol or ethyl acetate.Above-mentioned solvent can be used alone, is used in mixed way or is used in mixed way with water.Extract liquor with
The ratio of plant has no specific limitation, and in one embodiment, the ratio of extract liquor and plant is 1: 10 (W/W).
In extraction process, extraction temperature can have a little change with the difference of extract liquor.In one embodiment, available
Soaking at room temperature.In another embodiment, it can be heated to the reflux temperature (60~100 DEG C) of different extract liquors.Extraction time is about 2
Hour, long short end was depending on the extraction temperature of operation to 7 days.It, can be optionally by such as sodium chloride, dilute separately in extracting operation
Inorganic acid (such as dilute hydrochloric acid) or organic acid (such as vitamin C or tartaric acid) are added in extract liquor, to adjust the pH value of extract liquor.
Later, it is dried after being concentrated containing the extract of procyanidine active constituent, or can be optionally to above-mentioned extraction
Object is taken to carry out partial purification or Economical Purification.In one embodiment, partially purified method is the extract that will dry with 95%
Alcohol and/or methanol aqueous solution back dissolving, later, using the solvent extraction of opposed polarity, to remove partial impurities, such as first with non-
Polar solvent (such as n-hexane) removes lipid and apolar substance, then with chloroform and/or small point of ethyl acetate extraction removal
Sub- phenolic compound.Later, it will be concentrated and dried through the water layer after solvent extraction, you can the original flower that retrieval section more purifies
Green element substance.
If Economical Purification to be carried out, step may include above-mentioned through partially purified extraction with alcohol or methanol aqueous solution dissolving
Object is taken, then is put into molecular sieve tubing string.Later, it is purged with different solutions and/or mixed solution, carries out the pure of procyanidine
Change separation.In one embodiment, the sequence that different solutions purge with is:95% alcohol, 95% alcohol/methanol (1: 1, v/v), 50%
Methanol and 50% aqueous acetone solution.By each solution progress Fractional Collections for purging with liquid and purging with out.Later, with liquid chromatograph
Purified procyanidine in the solution that (280nm) detection purges with out.It collects difference and purges with the solution that liquid purges with out, can obtain
The procyanidine solution being distributed to different molecular weight.Later, by solution that above-mentioned different phase purges with out be less than 40 DEG C it
Temperature concentrates, and is freeze-dried, you can the procyanidine purified.In one embodiment, the molecular sieve tubing string purged with
For Sephadex LH-20 tubing strings (being purchased from the West Asias An Ma limited liability company of Germany).
The present invention has following chemical formula through above-mentioned procyanidine after purification, monomer.
In one embodiment, when R1 is OCH3, R2 OH, R3 H.In another embodiment, when R1 is OH, R2 is
H, R3 H.In another embodiment, when R1 is OH, R2 OH, R3 H.In another embodiment, when R1 is OH, R2 is
OH, R3 OH.In above-mentioned chemical formula, R4 can be 3- (α)-OH, 3- (β)-OH, 3- (α)-O-sugar or 3- (β)-O-sugar.
The monomer of above-mentioned procyanidine may include R the or S optical isomeric compounds in the position C2, C3 or C4.
It may include flavone compound, such as catechin (catechin), table in the monomer structure of above-mentioned procyanidine
Theine (epicatechin), epiafzelechin (epiafzelechin), gallocatechin (gallocatechin),
Galloepicatechin, epigallocatechin (epigallocatechin), gallates, flavonols (flavonols),
Flavandiols (flavandiols), leucocyanidin (leucocyanidins) or anthocyanidin (procynidins).One
In embodiment, the monomer of procyanidine may include flavan-3-alcohol (flavan-3-ol) or flavan derivatives.
The degree of polymerization of procyanidine of the present invention is between 2~30, preferably between 3~20.The monomer of procyanidine of the present invention can
It is connected with each other with C4, C8 carbon key, C4, C6 carbon key or C2, C7 oxygen key.The average molecular weight of procyanidine of the present invention between 600~
10,000。
In one embodiment, the procyanidine that the present invention purifies may include the procyanidine of the single degree of polymerization.In another reality
It applies in example, the procyanidine that the present invention purifies may include the procyanidine mixture of different polymerization degree.
The procyanidine that the present invention above-mentioned can extract is made one and deteriorates for slowing down liver cancer, improves liver function, improving liver
Fibrosis, improve hepatic sclerosis, improve liver inflammation and promote the regenerated pharmaceutical composition of damaged liver, may include procyanidine with
One pharmaceutically acceptable carrier or salt.
Pharmaceutically acceptable carrier may include, but be not limited to solvent, decentralized medium (dispersion medium),
It is coated (coating), antibacterial agent, antifungal agents, isosmoticity and absorption delay (absorption delaying) reagent
Or pharmacy applies compatilizer.For different modes of administration, pharmaceutical composition is configured to various appropriate agent using prior art method
Type (dosage form).
Pharmaceutically acceptable salt may include, but be not limited to inorganic salts or organic salt.Inorganic salts may include
Such as the alkali metal group salt of sodium, potassium or amine salt, such as magnesium or calcium salt alkaline earth salt, or such as zinc, aluminium or zirconates contain two
Valence or quadrivalent cation salt.Organic salt may include dicyclohexyl amine salt, methyl-D-glucosamine or such as arginine, rely ammonia
The amidates of acid, histidine or glutamine.
The administering mode of pharmaceutical composition (BEL-X) of the present invention may include taking orally, is non-oral, spraying through sucking
The mode of (inhalation spray) or implanted reservoir (implanted reservoir) is administered.Non-oral mode can
Including through subcutaneous (subcutaneous), intradermal (intracutaneous), intravenous (intravenous), intramuscular
(intramuscular), in intra-articular (intraarticular), artery (intraarterial), synovial bursa (chamber)
(intrasynovial), in breastbone in (intrasternal), subarachnoid space (intrathecal) or disease location
(intraleaional) injection or perfusion technique.
Peroral dosage form may include, but be not limited to lozenge, capsule, emulsion (emulsions), aqueous suspension (aqueous
Suspensions), dispersion liquid (dispersions) or solution.
Pharmaceutical composition (BEL-X) of the present invention can be applied to the treatment of various liver diseases through experiment test discovery, including
(1) by the caused liver cancer of chronic hepatitis b virus or hepatitis C virus infection, pharmaceutical composition (BEL-X) of the present invention can be single
Solely use or as other various cures auxiliary therapeutical agent, can improve and be promoted the liver function of liver cancer sufferer, slow down liver
Cancer deteriorates time-histories, and operability and success rate of operation can be carried out by improving liver cancer sufferer, reduced Postoperative recurrent rate, can be increased liver cancer sufferer
Survival rate with extend the time-to-live, meanwhile, can also promote the quality of the life of liver cancer sufferer.(2) pharmaceutical composition of the present invention
(BEL-X) it can be used alone or merge with other clinical treatment drugs using treating liver fibrosis sufferer.(3) drug of the present invention
Composition (BEL-X) be can be used alone or be merged with other clinical treatment drugs using treating liver inflammation sufferer, such as:Fat
Liver disease prevents the generation of hepatic sclerosis and liver cancer to improve its liver function.
Embodiment
Embodiment 1
1. the monomer structure of procyanidine polymer measures
The structure of procyanidin monomers is to detect (Gas Chrimatograph-Mass to thermally decompose gas chromatography mass spectrometry instrument
Spectrometry).The method of detection is that the purifying procyanidine (the voluntarily sample of purifying) of solid is placed directly within thermal decomposition
Gas chromatograph, gradually heating or the moment heating in a manner of wise temperature (50 DEG C to 500 DEG C) or the setting operation of single temperature,
The sample of heat resolve is sentenced through thermally decomposing the specific metal tube post separation of instrument through collection of illustrative plates caused by mass spectrograph detector
Make the monomer structure of procyanidine polymer.The mass spectrogram of procyanidine polymer and structural analysis be shown in Fig. 2 a with
2b.Wherein the left side of Fig. 2 b-e is the m/z values and its chemical constitution of Fig. 2 a wave crests, and the monomer that right side is left side wave crest
Parsing.The monomer structure molecular formula of the procyanidine polymer determined is as follows:
Wherein, R1For OCH3、R2For OH and R3For H or R1For OH and R2With R3It is all H or R1With R2It is all OH and R3For H,
Or R1、R2With R3It is all OH.And because the mass spectrum measured by thermal decomposition shows the peak containing glycocide signal, therefore estimate R4's
Composition may be 3- (α)-OH, 3- (β)-OH, 3- (α)-O-sugar or 3- (β)-O-sugar.
2. infrared Absorption spectrum analysis
It detects, the procyanidine sample and potassium chloride mixed pressuring plate of purifying as a result such as Fig. 3 institutes with penetration infrared spectrum
Show, wherein stronger absorption wave crest is 3412.38nm, 1610.57nm, 1521.40nm, 1441.14nm, 1284.86nm,
1100.88nm。
3. high performance liquid chroma- tography mass-spectrogram is analyzed
By the procyanidine sample of purifying, with efficient liquid chromatograph mass spectrometer (EFI spills positive/negative mass spectrograph, HPLC/ESI+,
HPLC/ESI-) (Micromass Quattro/Waters 2690) is detected, and detects the monomer of the procyanidine degree of polymerization 1 to 6
And polymer, and contain 164 glycocide (i.e. monomer molecule amount adds one to match glycan molecule amount 164).The procyanidine of purifying it
High performance liquid chroma- tography the positive/negative mass spectrogram of mass spectrum as shown in Fig. 4 a and 4b.
4. nuclear magnetic resonance carbon 13 (13C NMR) and hydrogen (1H NMR) atlas analysis
The procyanidine sample of purifying with carbon 13 (13C NMR) and hydrogen (1H NMR) nuclear magnetic resonance apparatus detection, carbon 13 (13C
NMR result) is as shown in Fig. 5 a-c.Wherein in 142-145.7ppm in addition to the wave crest of display doublet-doublet, not
Other wave crest, displaying monomer have anthocyanidin, and without delphinidin (delphindin), i.e. B rings have 3-OH substituent group persons,
It is identical as EGA/MS institute's analysis results herein.And R in figure 5b1=H or OH and R2=H or OH or OCH.
Foundation1HNMR and13The inspection collection of illustrative plates of CNMR shows, the monomer of the procyanidine macromolecule of present invention purifying link with
Based on 4-8.The connection unit of 4-8 and 4-6 is respectively as shown in Fig. 6 a and 6b.
5. medium assisted laser desorption ionization massspectrum (Matrix Assisted Laser Desorption
Ionization Time-of-Flight (MALDI-TOF)) analysis
The procyanidine molecular weight distribution of partial purification is measured with medium assisted laser desorption ionisation mass spectrometry.As a result
As shown in figs. 7 a-c.The result of detection shows that the molecular weight distribution of the procyanidine through partial purification is 500-5000, by molecule
The testing result of amount distribution shows that the degree of polymerization of presumption macromolecule is about 2-18.
Embodiment 2
The preparation (1) of the extract containing procyanidine
The root of mountain ramie medicinal material is cleaned with the stem for connecting root with water, is placed under natural environment dry.It will dry
Medicinal material afterwards is sliced to about 5mm thickness, be stored in 4 DEG C it is spare.The mountain ramie medicinal material stored for future use is taken, is ground, is taken with mill
It is less than the powder of mesh 20 (20mesh) after sieving.Later, 95% alcohol of 10 times of weight (1: 10, w/w) is added, is heated to reflux
2 hours (secondary altogether).After standing cooling rise again, the extract liquor risen again is collected, and is poured into centrifugation bag with centrifuge mistake
Filter.Later, filtered fluid is placed in temperature control to concentrate in the reduced pressure machine less than 40 DEG C, and utilizes freeze drier
Drying, you can obtain the extract containing procyanidine.
Embodiment 3
The preparation (2) of the extract containing procyanidine
Example 2 is stored in 4 DEG C of drying medicinal material, is ground with mill, is less than mesh 20 (20mesh) after taking sieving
Powder.Later, the reverse osmosis processing water (RO water) of 10 times of weight (1: 10, w/w) is added, is heated to reflux 2 hours (secondary altogether).
After standing cooling rise again, the extract liquor risen again is collected, and alcohol (95% to 50%) aqueous solution is added.It is stood after mixing cold
To be precipitated.Upper liquid is poured into centrifugation bag and is filtered with centrifuge.Later, by filtered fluid be placed in temperature control less than
It is concentrated in 40 DEG C of reduced pressure machine, and it is dried using freeze drier, you can obtain the extract containing procyanidine.
Embodiment 4
The purifying (1) of the extract containing procyanidine
N-hexane (1: 10, w/v) is added in extract of the embodiment 2 or 3 containing procyanidine and is heated to reflux (by Soxhelt
Apparatus) 6 hours, to remove the lipid in extract.Obtained solids is given birth to 70% methanol aqueous solution and/or 0.3 dimension
Plain C aqueous dissolutions are placed in temperature control and are concentrated in the reduced pressure machine less than 40 DEG C, to remove solvent.Later,
By condensation product be added chloroform (1: 1, chloroform:Condensation product, v/v), and vibrated 30 minutes (repeatedly extraction) with oscillator.
Water intaking layer addition ethyl acetate (1: 1, ethyl acetate:Water layer, v/v), oscillation 30 minutes (repeatedly extraction).It fetches water again and is placed on temperature
Degree control is concentrated in the reduced pressure machine less than 40 DEG C, and dries it using freeze drier, you can it is pure to obtain part
The procyanidine of change.
Embodiment 5
The purifying (2) of the extract containing procyanidine
Water/alcohol is added in extract of the embodiment 2 or 3 containing procyanidine and dissolves (1: 10, w/v).Later, be added just oneself
Alkane (1: 10, v/v) vibrates 30 minutes (repeatedly extraction), to remove the lipid in extract with oscillator.Acetic acid is added in layer of fetching water
Second fat (1: 1, ethyl acetate:Water layer, v/v), oscillation 30 minutes (repeatedly extraction).N-butanol (1: 10, v/ is added in layer of fetching water again
V), it is vibrated 30 minutes (repeatedly extraction) with oscillator.It fetches water again and is placed on temperature control in the reduced pressure machine less than 40 DEG C
It is concentrated, and it is dried using freeze drier, you can obtain partially purified procyanidine.
Embodiment 6
The purifying (3) of the extract containing procyanidine
By the partial purification procyanidine of 4 gained of embodiment, with molecular sieve col-umn chromatography (Gel Permeation
Chromatography, 4cm diameter x 45cm long Sephadex LH-20) carry out repurity.First, with difference
Polar solution is purged with, to remove impurity.Later, 2.5 grams of partially purified procyanidine are taken, with 95% alcohol of 0.5mL
Dissolve it.Then, dissolved sample is placed in molecular sieve tubing string, is continuously purged with a series of solvents (purging with liquid), and receive
The flowing lotion that collection different solvents (purging with liquid) purge with out.It is respectively 95% alcoholic solutions of 300mL, 95% wine of 300mL to purge with liquid
Essence/methanol (1/1, v/v), 50% aqueous acetone solution of 300mL methanol, 50% methanol aqueous solutions of 300mL and 300mL.In addition to
95% alcohol of 300mL purges with outside the flowing lotion that liquid purges with out, other each section of flowing lotion purged with out is placed in temperature control low
It is concentrated in 40 DEG C of reduced pressure machine, and it is dried using freeze drier, you can obtain partial purification or completely pure
The procyanidine of change.Later, by the substance after above-mentioned drying be stored in -20 DEG C it is spare.
Embodiment 7
Influence of the drug (BEL-X) on hepatitis B virus X trangenic mice induced hepatocellular carcinoma survival rates
Experimental animal:Animal parental generation introduces a collection used in experiment is BBRC in 20061The hepatitis B virus X delivered turns
The public affairs mouse of DNA rat C57BL/6J-HBx (A0112 line).
Experiment packet and experimental design:Mouse experiment group is divided into 6 groups, includes the control group (Non-Tg of non-transgenic mouse
Mock 9-20M), the control of drug control group (the Non-Tg BEL-X treated 9-20M), trangenic mice of non-transgenic mouse
3 groups of the drug test group (Tg BEL-X treated) of group (Tg mock 9-20M) and trangenic mice:Respectively at mouse September age
Play (Tg BEL-X treated 9-20M), (Tg BEL-X treated 12-20M) and (Tg from 15 monthly ages from 12 monthly ages
BEL-X treated 15-20M) start to give oral drugs BEL-X (pharmaceutical composition of the present invention) once daily, it is administered continuously
To 20 monthly ages.Control group (the Tg mock 9- of the control group (Non-Tg mock 9-20M) and trangenic mice of non-transgenic mouse
20M) from mouse September age, it is primary to give animal drinking water daily, continues to 20 monthly ages.The drug control group of non-transgenic mouse
(Non-Tg BEL-X treated 9-20M) also from mouse September age, it is primary to give oral drugs BEL-X daily, persistently gives
Medicine is to 20 monthly ages.The dosage of BEL-X drugs is 1,000mg/kg/ days.
Conclusion:
1. referring to Fig. 8, hepatitis B virus X trangenic mice public affairs mouse 100% will produce liver cancer at 20 monthly age, survive
Rate is about 64% (Tg mock 9-20M).And the survival rate of Different Month feeding drug BEL-X is respectively:9-20 monthly age (Tg
BEL-X treated 9-20M) 70%, 12-20 monthly ages (Tg BEL-X treated 12-20M) 100%, 15-20 monthly age (Tg
BEL-X treated 15-20M) 58%.
2. with Chi-Square discoveries for statistical analysis, hepatitis B virus X trangenic mice public affairs mouse are given at the 12-20 monthly ages
Medicine BEL-X, survival rate has significant difference up to 100% when 20 monthly age.
3.B Hepatitis virus X trangenic mice public affairs mouse can increase in early stage induced hepatocellular carcinoma feeding BEL-X generates hepatocarcinoma gene mouse
The survival rate of public mouse.
Embodiment 8
The influence that drug (BEL-X) slows down hepatitis B virus X trangenic mice liver cancer deterioration degrees
Experimental animal:Animal parental generation introduces a collection used in experiment is BBRC in 20061The hepatitis B virus X delivered turns
The public affairs mouse of DNA rat C57BL/6J-HBx (A0112 line).
Experiment packet and experimental design:Mouse experiment group is divided into 6 groups, includes the control group (Non-Tg of non-transgenic mouse
Mock 9-20M), the control of drug control group (the Non-Tg BEL-X treated 9-20M), trangenic mice of non-transgenic mouse
3 groups of the drug test group (Tg BEL-X treated) of group (Tg mock 9-20M) and trangenic mice:Respectively at mouse September age
Play (Tg BEL-X treated 9-20M), (Tg BEL-X treated 12-20M) and (Tg from 15 monthly ages from 12 monthly ages
BEL-X treated 15-20M) start to give oral drugs BEL-X (pharmaceutical composition of the present invention) once daily, it is administered continuously
To 20 monthly ages.Control group (the Tg mock 9- of the control group (Non-Tg mock 9-20M) and trangenic mice of non-transgenic mouse
20M) from mouse September age, it is primary to give animal drinking water daily, continues to 20 monthly ages.The drug control group of non-transgenic mouse
(Non-Tg BEL-X treated 9-20M) also from mouse September age, it is primary to give oral drugs BEL-X daily, persistently gives
Medicine is to 20 monthly ages.The dosage of BEL-X drugs is 1,000mg/kg/ days.
Measure the ratio of liver weight and weight:Animal is sacrificed and dissects and carry out liver (containing liver tumour) sampling.Institute's scale is obtained
Liver weight divided by mouse weight, you can obtain liver weight and the ratio (liver/Body weight) of weight.
Conclusion:
1. referring to Fig. 9, the liver weight of normal non-transgenic mouse (Non-Tg mock) and body weight ratio are about 5%, and Type B
Hepatitis virus X trangenic mice public affairs mouse (Tg mock) at 20 monthly age because generate liver cancer, therefore its liver weight risen to body weight ratio
13% or so, it is found with ANOVA statistical analyses, trangenic mice and the liver weight of normal non-transgenic mouse have significance difference with body weight ratio
It is different.
2. normal non-transgenic mouse feeding BEL-X continuous 1 year (9-20 monthly ages) (Non-Tg BEL-X treated 9-
It is 5% that 20M) liver weight is identical as non-medicine feed group as body weight ratio afterwards, shows that this drug has no effect to intact animal.
3.B Hepatitis virus X trangenic mice public affairs mouse are in Different Month feeding drug BEL-X discoveries, three groups of livers weights and weight
Ratio falls to 8% or so, and 9-20 monthly ages (Tg BEL-X treated 9-20M) and 12-20 monthly ages (Tg BEL-X
Treated 12-20M) administration group and non-administered group (Tg mock 9-20M) have notable statistical discrepancy.
Embodiment 9
Influence (1) of the drug (BEL-X) on its liver function of hepatitis B virus X trangenic mice induced hepatocellular carcinomas
Experimental animal:Animal parental generation introduces a collection used in experiment is BBRC in 20061The hepatitis B virus X delivered turns
The public affairs mouse of DNA rat C57BL/6J-HBx (A0112 line).
Experiment packet and experimental design:Mouse experiment group is divided into 6 groups, includes the control group (Non-Tg of non-transgenic mouse
Mock 9-20M), the control of drug control group (the Non-Tg BEL-X treated 9-20M), trangenic mice of non-transgenic mouse
3 groups of the drug test group (Tg BEL-X treated) of group (Tg mock 9-20M) and trangenic mice:Respectively at mouse September age
Play (Tg BEL-X treated 9-20M), (Tg BEL-X treated 12-20M) and (Tg from 15 monthly ages from 12 monthly ages
BEL-X treated 15-20M) start to give oral drugs BEL-X (pharmaceutical composition of the present invention) once daily, it is administered continuously
To 18 monthly ages.Control group (the Tg mock 9- of the control group (Non-Tg mock 9-20M) and trangenic mice of non-transgenic mouse
20M) from mouse September age, it is primary to give animal drinking water daily, continues to 20 monthly ages.The drug control group of non-transgenic mouse
(Non-Tg BEL-X treated 9-18M) also from mouse September age, it is primary to give oral drugs BEL-X daily, persistently gives
Medicine is to 18 monthly ages.The dosage of BEL-X drugs is 1,000mg/kg/ days.
Liver function ICG detections:After ten minutes with indocyanine green (indocyanine green, ICG) intravenous injection, ICG is measured
The concentration (mg/dl) being stranded in blood, using the index as liver function.This experiment carries out 2 times altogether, respectively at 12 monthly age of mouse and
It is executed when 18 monthly age.
Conclusion:
1. please referring to the following table 1, the metabolic cost of 18 monthly age normal non-transgenic mouse (Non-Tg mock 9-20M) ICG is
2.25 ± 0.89mg/dl, this result is with 18 monthly age feeding BEL-X groups (Non-Tg BEL-X treated 9-20M) without significance difference
It is different.
2.B Hepatitis virus X trangenic mice public affairs mouse (Tg mock 9-20M) are at 18 monthly age because generating liver cancer, therefore its ICG
Be metabolized it is slow be extended down to 4.46 ± 1.17mg/dl, found with nonparametric statistical analyses, trangenic mice non-turns base with normal
Because of the ICG metabolism tool significant differences of mouse.
3.B Hepatitis virus X trangenic mice public affairs mouse are in three groups of Different Month feeding drug BEL-X discoveries, three groups of ICG generations
It is lower than non-administered group (Tg mock 9-20M) to thank to rate, and starts feeding drug BEL-X (Tg BEL-X treated in September age
9-20M) there is with non-administered group (Tg mock 9-20M) notable statistical discrepancy, display BEL-X can improve the liver function of liver cancer animal
Energy.
Table 1
Group | ICG concentration (mg/dl) in blood when 18 monthly age |
Non-Tg mock 9-20M | 2.25±0.89 |
Non-Tg BEL-X treated 9-20M | 2.13±0.92 |
Tg mock 9-20M | 4.46±1.17 |
Tg BEL-X treated 9-20M | 2.63±0.76 |
Tg BEL-X treated 12-20M | 3.47±0.77 |
Tg BEL-X treated 15-20M | 3.87±0.72 |
Embodiment 10
Influence (2) of the drug (BEL-X) on its liver function of hepatitis B virus X trangenic mice induced hepatocellular carcinomas
Experimental animal:Animal parental generation introduces a collection used in experiment is BBRC in 20061The hepatitis B virus X delivered turns
The public affairs mouse of DNA rat C57BL/6J-HBx (A0112 line).
Experiment packet and experimental design:Mouse experiment group is divided into 6 groups, including non-transgenic mouse control group (, Non-Tg
Mock 9-20M), the control of drug control group (the Non-Tg BEL-X treated 9-20M), trangenic mice of non-transgenic mouse
3 groups of the drug test group (Tg BEL-X treated) of group (Tg mock 9-20M) and trangenic mice:Respectively at mouse September age
Play (Tg BEL-X treated 9-20M), (Tg BEL-X treated 12-20M) and (Tg from 15 monthly ages from 12 monthly ages
BEL-X treated 15-20M) start to give oral drugs BEL-X (pharmaceutical composition of the present invention) once daily, it is administered continuously
To 20 monthly ages.Control group (the Tg mock 9- of the control group (Non-Tg mock 9-20M) and trangenic mice of non-transgenic mouse
20M) from mouse September age, it is primary to give animal drinking water daily, continues to 20 monthly ages.The drug control group of non-transgenic mouse
(Non-Tg BEL-X treated 9-20M) also from mouse September age, it is primary to give oral drugs BEL-X daily, persistently gives
Medicine is to 20 monthly ages.The dosage of BEL-X drugs is 1,000mg/kg/ days.
Liver function enzyme glutamic-pyruvic transaminase (ALT) is detected with glutamic-oxalacetic transaminease (AST):All mouse monthly taking periodic blood (under
Jaw or Culling heart blood) once, whole blood stands 30 minutes or more at room temperature in eppendorf.After blood coagulation 10 are centrifuged with 1,800g
Minute.After centrifugation, serum is moved in new eppendorf in -20 DEG C of storages to the detection same day.With wet type serum biochemistry instrument
(HITACHI 7080) measures ALT and AST values in serum.Due to hepatitis B virus X trangenic mice public affairs mouse generate liver pathological changes with
The animal monthly age has relevance, therefore by liver function Index A LT and AST measured by every group of animal of 9-20 monthly ages, by September age, every 3
Hybrid analysis in a month.
Conclusion:
1. please referring to Fig.1 0,11, normal non-transgenic mouse (Non-Tg mock 9-20M) and hepatitis B virus X transgenosis
Mouse (Tg mock 9-20M) is variant since the 12nd monthly age, and normal non-transgenic mouse feeding BEL-X (Non-Tg BEL-X
Treated 9-20M) with non-administered group (Non-Tg mock 9-20M) liver function index without significant difference.
2.B Hepatitis virus X trangenic mices find that three groups of ALT and AST ratio is not in Different Month feeding drug BEL-X
Administration group (Tg mock 9-20M) is low, and 9-20 monthly ages (Tg BEL-X treated 9-20M) and 12-20 monthly ages (Tg BEL-
X treated 12-20M) for administration group with non-administered group (Tg mock 9-20M) with notable statistical discrepancy, display BEL-X can
To be effectively improved the liver function of liver cancer animal.
Embodiment 11
Drug (BEL-X) induces chemicals DEN the influence (1) of rat liver fibrosis
Experiment packet and experimental design:By 8 weeks big Wistar rats difference feeding diethylnitrosamine (diethyl
Nitrosamine, DEN) (100ppm makes an addition in drinking-water and gives) 6 weeks (D6 groups) and 9 weeks (D9 groups), generate liver fibre to induce
Dimensionization and liver cancer.Other two groups of animals also give BEL-X drugs (1000mg/kg body weight) simultaneously in feeding DEN and (add
It is added on daily feeding in feed, 6 weeks continuous (D6H6 groups) and 9 weeks (D9H9 groups)).Animal carries out liver cancer degree in different time points
Analysis.Control group whole process does not give any drug.Each experimental group respectively has 10 rats.Liver fibrosis/liver cancer degree analyzing with
Interpretation after staining pathologic section, and help with hydroxyproline biochemical analysis.It measures hydroxyproline content rising in liver and can be used as liver
The index of fibrosis.Acquisition each group animal's liver carries out hydroxyproline content measurement in different time points.Later, liver is carried out
Slice carries out α-SMA immunostained for analysis.It is also liver fibrosis that α-smooth-muscle-actin (α-SMA) content, which rises,
Another index.At the 9th week, acquisition each group animal's liver carries out α-smooth-muscle-actin immunostainings, and utilizes micro-
Mirror carries out the observation of liver cell, calculates the cell concentration containing this label.
Conclusion:
1. please refer to Fig.1 2, continuously give 9 weeks animal groups of DEN (D9 groups), in liver hydroxyproline content it is notable on
It rises, display DEN successfully induces liver fibrosis, but the also experimental group (D9H9 groups) of feeding BEL-X simultaneously, and hydroxyproline content is then
It is remarkably decreased, display BEL-X has the function of protecting liver from the liver fibrosis caused by chemical substance DEN.
2. please refer to Fig.1 3,9 weeks animal groups of DEN (D9 groups) are continuously given, α-smooth-muscle- in liver
Actin contents significantly rise, and display DEN successfully induces liver fibrosis, but simultaneously also the experimental group (D9H9 groups) of feeding BEL-X its
Content is remarkably decreased, and display BEL-X has the function of that liver is protected to cause liver fibrosis from chemical substance DEN.
3. in addition, continuous give DEN 6 weeks while the also experimental group (D6H6 groups) of feeding BEL-X, α-smooth-
Muscle-actin contents are also remarkably decreased, and display BEL-X has early protection liver from the liver fibre caused by chemical substance DEN
The function of dimensionization.
Embodiment 12
Drug (BEL-X) induces chemicals DEN the influence (2) of rat liver fibrosis
Experiment packet and experimental design:By 8 weeks big Wistar rats difference feeding diethylnitrosamine (diethyl
Nitrosamine, DEN) (100ppm makes an addition in drinking-water and gives), generate liver fibrosis and liver cancer to induce.Other three groups dynamic
Object also gives BEL-X drugs (1000mg/kg body weight) in feeding DEN and (makes an addition to daily feeding in feed, divide simultaneously
Not in the 3-6 weeks, the 6-9 weeks and the 9-12 weeks feeding).Animal carries out liver cancer degree analyzing in appropriate time point.Control group
(DEN) during being feeding DEN, whole process is not administered.Each experimental group respectively has 10 rats.Liver fibrosis/liver cancer degree analyzing
Differentiated with ocular estimate, and helped with hydroxyproline biochemical analysis.It measures hydroxyproline content rising in liver and can be used as liver fibrosis
Index.Each group animal's liver was acquired at the 12nd week carries out hydroxyproline content measurement.
Conclusion:
1. please refer to Fig.1 4, continuously give 9 weeks animal groups of DEN (DEN), in liver hydroxyproline content it is notable on
It rises, display DEN successfully induces liver fibrosis, but experimental group (the 3-6 weeks (DEN- of period feeding BEL-X is induced in early stage DEN
BEL-X 3-6) and the 6-9 weeks (DEN-BEL-X 6-9), hydroxyproline content is remarkably decreased, and display BEL-X, which has, to reverse
The function of liver fibrosis caused by chemical substance DEN.
Embodiment 13
Drug (BEL-X) induces chemicals DEN the influence of rat liver fibrosis survival rate
Experiment packet and experimental design:By 8 weeks big Wistar rats difference feeding diethylnitrosamine (diethyl
Nitrosamine, DEN) (50ppm makes an addition in drinking-water and gives) 10.5 weeks continuous, generate liver fibrosis and liver cancer (B to induce
Group).Respectively at 0-10.5 weeks (C groups), 3-10.5 weeks (D groups), 6-10.5 weeks (E groups) or stopping feeding simultaneously in feeding DEN
BEL-X drugs (1000mg/kg body weight) are made an addition to daily feeding in feed by (F groups) 0-3 weeks after DEN.Animal in
Appropriate time point carries out liver cancer degree analyzing.Control group is whole not to any drug (A groups).It is dead that animal is noted down during experiment
It dies, with nonparametric statistical analysis each group survival rates.
Conclusion:
1. please referring to Fig.1 5, each group survival rate was analyzed at (94 days) the 13.5th week and is found, individually give DEN (B groups) survivals
Rate only surplus 40% or so, and each group of different time feeding BEL-X has very high survival rate (> 80%), shows BEL-X
The survival rate of liver fibrosis and liver cancer can be dramatically increased.
2. please referring to Fig.1 6, BEL-X drugs are given again 3 weeks (F groups) after analyzing DEN induced hepatocellular carcinomas at (104 days) the 15th week
Survival rate find:(74-94 days) can not only maintain the survival of animal 100%, stopping to give BEL-X medicines during BEL-X is administered
(95-99 days) can still maintain no death rate after object 5 days.Find that its survival rate 62% remains above individually at the 15th week (104 days)
DEN (B groups) is given in the survival rate 40% of the 13.5th week (94 days), shows that BEL-X can not only prolong hepatic sclerosis with liver cancer animal
Its long time-to-live, it can also dramatically increase survival rate.
Embodiment 14
Chemicals DEN induces impaired rear influence (1) of the drug (BEL-X) on its liver regeneration of rat liver
Experiment packet and experimental design:By 8 weeks big Wistar rats difference feeding diethylnitrosamine (diethyl
Nitrosamine, DEN) and (100ppm, make an addition to drinking-water in give) it is 9 weeks continuous, to induce generation Hepatic fibrosis and cirrhosis
(non-administered group).In addition at the 6-9 weeks, adding BEL-X drugs (was divided into BEL-X high dose groups (1,000mg/kg body simultaneously
Weight) with BEL-X low dose groups (250mg/kg body weight)) the daily feeding in feed.Complete feeding drug
Afterwards, 50% lobe of the liver was cut off in the 9th week, and in collecting liver specimens two days later, carries out slice and is dyed with H&E.Later, in microscope
The mitosis of lower observation liver cell, using as liver regeneration foundation.The mitosis of liver cell calculates as follows:Every animal is extremely
Rare 3 liver slices are each sliced 10 visuals field, count mitotic cell number in the case where microscope amplifies 400X multiplying powers, most
The average value of every group of animal is sought afterwards.
Conclusion:
1. please referring to the following table 2, chemicals DEN induces liver fibrosis and cuts discovery, non-administered group liver with progress liver after liver cancer
Dirty mitosis number (7.6 ± 4.6) relatively gives the mitosis number of high or low 3 weeks animal's livers of dosage BEL-X drugs simultaneously
(12 ± 5.5 or 13.0 ± 5.6) are much lower, show when chemicals DEN causes hepatic injury, BEL-X have significantly make liver
Regenerated function.
Table 2
Group | Mitosis number |
BEL-X high dose groups | 12.0±5.5 |
BEL-X low dose groups | 13.0±5.6 |
Non-administered group | 7.6±4.6 |
Embodiment 15
Chemicals DEN induces impaired rear influence (2) of the drug (BEL-X) on its liver regeneration of rat liver
Experiment packet and experimental design:By 8 weeks big Wistar rats difference feeding diethylnitrosamine (diethyl
Nitrosamine, DEN) and (100ppm, make an addition to drinking-water in give) it is 9 weeks continuous, to induce generation Hepatic fibrosis and cirrhosis
(DEN groups).In addition BEL-X drugs (1,000mg/kg body weight) were added simultaneously at the 6-9 weeks to feed daily in feed
It eats (BEL-X groups).In addition non-feeding DEN and BEL-X person's (control group) carry out identical operation.After completing feeding drug, in the 9th
After week is checked with nuclear magnetic resonance photography, 30% lobe of the liver is cut off.Second of nuclear magnetic resonance photography is carried out after two weeks to check and dissect it.
Animal dead is noted down during experiment.Each group animal eating time and food ration are observed upon completing the procedure, and calculate each group animal
Survival rate.
Conclusion:
1. please referring to Fig.1 7, illustrate the regeneration ratio of liver volume.Its liver regeneration total amount of the control rats of normal hepatocytes is to cut
Except the 92 ± 11% of amount, liver cirrhosis group (DEN groups) is the 32 ± 7% of resection, and 79 that treatment group's (BEL-X groups) is resection
± 6%.The liver regeneration situation for the treatment of group's (BEL-X groups) is obviously preferred compared with liver cirrhosis group (DEN groups), with control group then without statistically
Difference.
2. please referring to the following table 3, liver cirrhosis animal is after liver cuts, and obviously compared with control group, (11 is small for eating time (27 hours)
When) extend many, and eating time (16 hour) of the BEL-X groups after liver cuts is considerably less than liver cirrhosis group (DEN groups).Another liver is hard
The food ration (42%) of change group (DEN groups) differs a lot of with control group (91%), and the food ration (83%) of BEL-X groups is also apparent
Higher than liver cirrhosis group (DEN groups), with control group indifference.This indicates that it is good that BEL-X drugs cut postoperative tool to liver cirrhosis animal liver
It is good to influence, food-intake can be increased and reduce eating time.
3. in addition, the survival rate of liver cirrhosis animal only 55% is survived however, when liver cirrhosis animal has feeding BEL-X
Rate is then identical as control group, up to 100%, it has thus been shown that BEL-X drugs can increase survival rate really.
Table 3
Although the present invention has been disclosed as a preferred embodiment, however, it is not to limit the invention, any to be familiar with this
Those skilled in the art, without departing from the spirit and scope of the invention, when can change and retouch, therefore the protection domain of the present invention is when regarding
Afterwards subject to attached those as defined in claim.
Claims (8)
1. a kind of purposes of pharmaceutical composition in the regenerated drug of damaged liver that manufacture promotes Diethylnitrosamine-induced Hepatocarcinoma of Rat,
Described in composition include:
The monomer of a effective amount of procyanidine, the procyanidine has following chemical formula:
Wherein, work as R1For OCH3When, R2For OH, R3For H, work as R1For OH when, R2For H, R3For H, or work as R1For OH when, R2For OH, R3
For OH, R4For 3- (α)-OH, 3- (β)-OH, 3- (α)-O-sugar or 3- (β)-O-sugar, wherein the list of the procyanidine
Body is connected with each other with C4, C8 carbon key, C4, C6 carbon key or C2, C7 oxygen key and the degree of polymerization of the procyanidine is between 2~30;
And
Pharmaceutically acceptable carrier or salt,
The wherein described pharmaceutically acceptable salt class includes sodium salt, sylvite, amine salt, magnesium salts, calcium salt, zinc salt, aluminium salt, zirconates, two
Cyclohexylamine salt, methyl-D-glucamine salt, arginine salt, lysine salt, histidine salt or glutamy amine salt.
2. purposes according to claim 1, wherein the monomer of the procyanidine is included in the R or S of the position C2, C3 or C4
Optical isomeric compound.
3. purposes according to claim 1, wherein the monomer of the procyanidine includes flavone compound.
4. purposes according to claim 3, wherein the flavone compound includes catechin (catechin), table catechu
Plain (epicatechin), epiafzelechin (epiafzelechin), gallocatechin (gallocatechin),
Galloepicatechin, epigallocatechin (epigallocatechin), gallates, flavonols (flavonols),
Flavandiols (flavandiols), leucocyanidin (leucocyanidins) or anthocyanidin (procynidins).
5. purposes according to claim 1, wherein the monomer of the procyanidine includes flavan-3-alcohol (flavan-3-
ol)。
6. purposes according to claim 1, wherein the procyanidine is extracted from a plant.
7. purposes according to claim 6, wherein the plant includes Ericaceae (Ericaceae), the rose family
(Rosaceae), the plant of Pinaceae (Pinaceae), Vitaceae (Vitaceae) or Urticaceae (Urticaceae).
8. purposes according to claim 7, wherein the plant of the Urticaceae (Urticaceae) includes mountain ramie.
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CN104774909A (en) * | 2014-10-17 | 2015-07-15 | 江苏大学 | Method for analysis of proanthocyanidins induced liver cancer cell autophagic death and application |
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CN114712386A (en) * | 2021-03-31 | 2022-07-08 | 贝尔克斯生技股份有限公司 | High polymeric proanthocyanidin composition and its application |
WO2022205137A1 (en) * | 2021-03-31 | 2022-10-06 | 贝尔克斯生技股份有限公司 | Polymeric proanthocyanidin composition and application thereof |
Also Published As
Publication number | Publication date |
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ES2668785T3 (en) | 2018-05-22 |
PL2689777T3 (en) | 2018-08-31 |
KR101981378B1 (en) | 2019-05-22 |
EP2689777B1 (en) | 2018-03-28 |
EP2689777A2 (en) | 2014-01-29 |
AU2011362905B2 (en) | 2015-11-12 |
CA2830616A1 (en) | 2012-09-27 |
RU2561688C2 (en) | 2015-08-27 |
JP2014508785A (en) | 2014-04-10 |
CA2830616C (en) | 2017-02-21 |
CN103442709A (en) | 2013-12-11 |
WO2012126178A3 (en) | 2012-11-22 |
RU2013146602A (en) | 2015-04-27 |
SG193486A1 (en) | 2013-10-30 |
EP2689777A4 (en) | 2014-09-17 |
KR20160143868A (en) | 2016-12-14 |
KR20140020966A (en) | 2014-02-19 |
DK2689777T3 (en) | 2018-05-22 |
NO2689777T3 (en) | 2018-08-25 |
WO2012126178A2 (en) | 2012-09-27 |
AU2011362905A1 (en) | 2013-10-31 |
JP6166251B2 (en) | 2017-07-19 |
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